New Therapeutic Options for Bile Acid Malabsorption Diarrhea

695

Liver News Column Page 1 of 4

New therapeutic options for bile acid malabsorption diarrhea

Alejandro Valencia-Rodríguez1, Jorge Aquino-Matus1, Alfonso Vera-Barajas1, Xingshun Qi2, Nahum Méndez-Sánchez1,3

1Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; 2Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, China; 3Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico Correspondence to: Nahum Méndez-Sánchez, MD, MSc, PhD. Liver Research Unit, Medica Sur Clinic and Foundation, Puente de Piedra 150, Col. Toriello Guerra, ZP. 14050, Mexico City, Mexico. Email: [email protected]; [email protected].

Submitted Aug 30, 2019. Accepted for publication Sep 16, 2019. doi: 10.21037/atm.2019.09.112 View this article at: http://dx.doi.org/10.21037/atm.2019.09.112

We have read with great interest the work published ileal dysfunction) there are included patients with chronic recently by Kårhus et al. (1) where they describe the pancreatitis where alterations in the secretion of bicarbonate efficacy of the glucagon-like peptide-1 (GLP-1) agonist coexist, in celiac disease where atrophy of the intestinal Liraglutide in two patients diagnosed with severe bile acid mucosa is seen, in postvagotomy patients where an increase malabsorption (BAM) by causing a complete remission of in GI motility is associated and in postcholecystectomy symptoms. patients due to impaired enterohepatic circulation. In 1972, Hofmann and Poley (2) studied 9 patients with Regardless the clinical spectrum of BAM, in all 3 types intestinal resection and bile acid diarrhea (BAD) to define there is an alteration in the transport and receptors of BAs the importance of BAM in the pathogenesis of chronic in the intestine due to a modification of the BAs pool (5) diarrhea in this type of patients, as well as the benefit shown (Figure 1). using cholestyramine and dietary changes. They found that Despite being a frequent condition among patients with resections of <1 meter responded well to treatment with chronic diarrhea, it is still an underdiagnosed condition. bile acid sequestrants (BAS) while those who had resections Different methods have been used to try to diagnose BAM, of >1 meter did not have benefits with the use of BAS the best method currently described is the 75-selenium presenting even more episodes of diarrhea and steatorrhea, homocholic acid taurine (SeHCAT) test. It is a nuclear but they responded well to dietary changes by replacing medicine investigation considered to be the gold standard long-chain triglycerides with medium-chain triglycerides. for the diagnosis of BAM by providing a quantitative It is currently known that BAD is one of the most assessment to estimate the severity and the possible frequent causes associated with chronic diarrhea (diarrhea response to therapy (6). From the work of Hoffman and >4 weeks). It is estimated that in developed countries 5% Poley, the BAS (cholestyramine, colestipol and colesevelam) of the population has chronic diarrhea, and approximately were considered the treatment of choice for this disease 25–33% are secondary to BAD (3). Globally, a prevalence although its therapeutic success has been questioned. BAS of BAD of 1% is estimated (4). For its classification BAM are polymeric resins with the ability to bind to BAs in the has been divided into 3 types (5): in type 1 (secondary to an small intestine, reducing their absorption and increasing ileal dysfunction) it mainly includes patients with Crohn’s their elimination through feces. This causes a de novo disease and/or intestinal resection. The mechanism involved synthesis at the liver and a decrease in plasmatic LDL-C is an alteration in the absorption of bile acids (BAs). In type concentration (7). BAS are also involved in triglyceride 2 (idiopathic) it generally occurs in patients with irritable metabolism by increasing plasmatic VLDL concentrations, bowel disease (IBD), the mechanisms predominantly this effect is partly mediated by Farnesoid X receptor (FXR), involved in this type are alterations in gastrointestinal (GI) considered as the main nuclear receptor that regulates BAs motility and intestinal dysbiosis in post-infectious diarrhea. synthesis and other compounds such as glucose, lipids and In type 3 (secondary to GI disorders not associated with aminoacids (7). The treatment with BAS changes the BAs

© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2019;7(22):695 | http://dx.doi.org/10.21037/atm.2019.09.112 Page 2 of 4 Valencia-Rodrígue et al. New therapeutic options for BAM diarrhea pool making them less effective to activate FXR (8). since it has been suggested that GI motility is accelerated Furthermore, in the last decade it has been seen in intestinal dysbiosis while suppressing the expression of suggested that BAS influence glucose metabolism by GLP-1 receptor in myenteric neural cells (13). Another changing the BAs pool obtained with the treatment of these association that would be important to investigate in those drugs which can activate with greater affinity the G protein- patients is the role that GLP-1 has on apical sodium- coupled bile acid receptor 1 (TGR5). This receptor is bile transporter (ASBT). It is known that when there is involved in the metabolism of BAs in an independent way of an increase of BAs in postprandial state, FXR inhibits the FXR and fibroblast growth factor-19 (FGF-19). Once BAs expression of ASBT and promotes the expression of ileal activate TGR5, internalization of the receptor is promoted bile acid-binding protein (IBABP) thus preventing the by increasing intracellular levels of cAMP and activation of excessive flux of BAs into the liver and decreasing BAs protein kinase A stimulating the intestine L cells to release synthesis by inhibiting CYP7A1 avoiding cytotoxicity (15) GLP-1. This theory is supported by an experimental study (Figure 1). However, the relationship between GLP-1 and carried out in rats with type 2 diabetes mellitus (T2DM) ASBT has not been established. which received treatment with BAS, resulting in an increase As mentioned before, FXR plays an important role in in the expression of GLP-1, YY peptide and insulin release the pathophysiology of BAM, so it has also been considered compared with the control group (9). In addition, in another as a therapeutic target. In 2018, Hvas et al. (16) published clinical study with patients with T2DM treated with BAS, a a case report where they described the effectiveness in the postprandial increase in GLP-1 was seen at 2 hours (10). use of obeticholic acid in a patient with severe BAM and In this case series published by Kårhus et al. (1) the antecedent of Crohn´s disease. Obeticholic acid is a both patients were taking liraglutide for presenting the selective FXR agonist generally used for the treatment of comorbidities of overweight and T2DM respectively. primary biliary cirrhosis. For the management of diarrhea Although they remitted the BAD episodes, in the second in this patient, the use of BAS was first resorted without case it was observed that 7 months after starting treatment, obtaining any significant clinical effect, the use of liraglutide a SeHCAT test was repeated showing 5% persistence so it was continued without improvement and finally the use would be important to evaluate this situation in detail. of obeticholic acid was administered presenting a clinical improvement within a few days. In this case the therapeutic failure of liraglutide might be In this context, how can we explain the clinical explained by the type of patient, since having the diagnosis improvement of GLP-1 in these patients? of Crohn’s disease (BAM type 1) made it impossible to GLP-1 is a human incretin secreted basolaterally by L-cells absorb BAs despite the motility effects caused by agonism of in response to various stimuli like glucose, aminoacids, GLP-1. The obeticholic acid by agonizing FXR decreased BAs and gut microbiome (11). The abundance of GLP-1 the synthesis of hepatic BAs leading to the remission secreting L-cells increases towards the distal end of the GI of BAM by decrease in the BAs pool. This could show tract (12). Glucose and aminoacids activate small intestinal that depending on the type of BAM, it would be the best L-cells whereas colonic L-cells express receptors for BAs. therapeutic tool for their control, despite this, none of the GLP-1 receptors have also been detected in the myenteric previously mentioned studies have the level of evidence plexi in the GI tract which act as a neural regulator of gut enough to suggest one treatment over another. contractile activity (13). In the upper part of the GI tract, In conclusion, BAM is a frequent cause of chronic GLP1 appears to have a mollifying effect on gut function. diarrhea which currently does not have a specific first- Using vagal neural pathways, GLP-1 has been shown to line treatment, the pathophysiological mechanisms in delay gastric emptying and small intestinal secretion and which BAM is involved at this time are better understood. motility, whereas in colon it increased colonic transit, also However, the treatment for BAM remains a clinical through vagal signaling (11). In a clinical trial in which a challenge in real life. The results of Kårhus et al.’s study (1) synthetic GLP-1 analogue was administered to a mixed open a new line of research to explore more effective new group of 99 IBD patients, anti-spasmodic and pain-relieving treatments such as the GLP-1 agonists. In future studies, effects were reported in these patients vs. placebo group (14). time and dose-dependent clinical trials are necessary to find Gut microbiota should also be studied in patients with BAM out the efficacy, safety and tolerability of this drug.

© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2019;7(22):695 | http://dx.doi.org/10.21037/atm.2019.09.112 Annals of Translational Medicine, Vol 7, No 22 November 2019 Page 3 of 4

MDRP2 FXR Bile canaliculi

ABST

BSEP TGR5

ABST GLP-1

FXR Enterocyte

NTCP ABBT IBABP L Hepatocyte U FGF19 M E N PORTAL VEIN OSTα/β

Figure 1 BAs transporters through enterohepatic circulation. In the intestine, specifically distal ileum, BAs are transported within the enterocyte by the action of ASBT, once inside, BAs activate FXR thereby inducing the expression of FGF-19 and by an independent way, BAs activate TGR-5 promoting intestine L cells to release GLP-1. In the enterocyte, the IBABP carriages the BAs to the portal vein, at this point the OSTα and OSTβ facilitate their passage to the hepatocyte where NTCP is the primarily responsible for the uptake of BAs from the sinusoids. In the hepatocyte, BAs are conjugated and then transported through the bile canaliculi via BSEP, subsequently MDRP2 delivers conjugates BAs to the gallbladder. This whole process conforms the enterohepatic circulation. However, in BAM, there is an alteration in the BAs pool making them less effective to activate FXR and therefore FGF-19. This causes modifications on BAs transporters, mainly ASBT and IBABP producing a decrease on its absorption in the distal ileum leading to a spillover into the colon. At this point there is a greater activation of TGR-5 increasing the release of GLP-1 by intestinal L cells causing a decrease in gastrointestinal motility. BAs, bile acids; ASBT, apical sodium bile acid transporter; FXR, Farnesoid X receptor; FGF-19, fibroblast growth factor-19; TGR-5, G protein- coupled bile acid receptor 1; GLP-1, glucagon like peptide-1; IBABP, ileal bile acid-binding protein; OSTα/β, organic solute transporter alpha/beta; NTCP, Na+ taurocholate cotransporting polypeptide; BSEP, bile salt export pump; MDRP2, multidrug resistance protein 2; BAM, bile acid malabsorption.

Acknowledgments References

This study was supported in part by a grant from Medica 1. Kårhus ML, Brønden A, Røder ME, et al. Remission of Sur Clinic and Foundation. Bile Acid Malabsorption Symptoms Following Treatment With the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide. Gastroenterology 2019;157:569-71. Footnote 2. Hofmann AF, Poley JR. Role of bile acid malabsorption Conflicts of Interest: The authors have no conflicts of interest in pathogenesis of diarrhea and steatorrhea in patients to declare. with ileal resection: i. response to cholestyramine or replacement of dietary long chain triglyceride by medium Ethical Statement: The authors are accountable for all chain triglyceride. Gastroenterology 1972;62:918-34. aspects of the work in ensuring that questions related 3. Vijayvargiya P, Camilleri M. Current Practice in the to the accuracy or integrity of any part of the work are Diagnosis of Bile Acid Diarrhea. Gastroenterology appropriately investigated and resolved. 2019;156:1233-8.

© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2019;7(22):695 | http://dx.doi.org/10.21037/atm.2019.09.112 Page 4 of 4 Valencia-Rodrígue et al. New therapeutic options for BAM diarrhea

4. Camilleri M. Bile Acid diarrhea: prevalence, pathogenesis, 11. O’Malley D. Endocrine regulation of gut function - a role and therapy. Gut Liver 2015;9:332-9. for glucagon-like peptide-1 in the pathophysiology of 5. Barkun AN, Love J, Gould M, et al. Bile acid irritable bowel syndrome. Exp Physiol 2019;104:3-10. malabsorption in chronic diarrhea: pathophysiology and 12. Steinert RE, Feinle-Bisset C, Asarian L, et al. Ghrelin, treatment. Can J Gastroenterol 2013;27:653-9. CCK, GLP-1, and PYY(3-36): Secretory Controls and 6. Fani B, Bertani L, Paglianiti I, et al. Pros and Cons of the Physiological Roles in Eating and Glycemia in Health, SeHCAT Test in Bile Acid Diarrhea: A More Appropriate Obesity, and After RYGB. Physiol Rev 2017;97:411-63. Use of an Old Nuclear Medicine Technique. Gastroenterol 13. Yang M, Fukui H, Eda H, et al. Involvement of gut Res Pract 2018;2018:2097359. microbiota in association between GLP-1/GLP-1 receptor 7. Massafra V, van Mil SWC. Farnesoid X receptor: A expression and gastrointestinal motility. Am J Physiol “homeostat” for hepatic nutrient metabolism. Biochim Gastrointest Liver Physiol 2017;312:G367-73. Biophys Acta Mol Basis Dis 2018;1864:45-59. 14. Hellström PM, Hein J, Bytzer P, et al. Clinical trial: 8. Trabelsi MS, Daoudi M, Prawitt J, et al. Farnesoid X the glucagon-like peptide-1 analogue ROSE-010 for receptor inhibits glucagon-like peptide-1 production by management of acute pain in patients with irritable bowel enteroendocrine L cells. Nat Commun 2015;6:7629. syndrome: a randomized, placebo-controlled, double-blind 9. Chen L, McNulty J, Anderson D, et al. Cholestyramine study. Aliment Pharmacol Ther 2009;29:198-206. reverses hyperglycemia and enhances glucose-stimulated 15. Neimark E, Chen F, Li X, et al. Bile acid-induced glucagon-like peptide 1 release in Zucker diabetic fatty negative feedback regulation of the human ileal bile acid rats. J Pharmacol Exp Ther 2010;334:164-70. transporter. Hepatology 2004;40:149-56. 10. Suzuki T, Oba K, Igari Y, et al. Colestimide lowers 16. Hvas CL, Ott P, Paine P, et al. Obeticholic acid for severe plasma glucose levels and increases plasma glucagon-like bile acid diarrhea with intestinal failure: A case report PEPTIDE-1 (7-36) levels in patients with type 2 diabetes and review of the literature. World J Gastroenterol mellitus complicated by hypercholesterolemia. J Nippon 2018;24:2320-26. Med Sch 2007;74:338-43.

Cite this article as: Valencia-Rodríguez A, Aquino-Matus J, Vera-Barajas A, Qi X, Méndez-Sánchez N. New therapeutic options for bile acid malabsorption diarrhea. Ann Transl Med 2019;7(22):695. doi: 10.21037/atm.2019.09.112